Process for the preparation of immunogens or diagnostic reagents, and immunogens or diagnostic reagents thereby obtainable

ABSTRACT

A process for the preparation of immunogens or diagnostic reagents that mimic an antigen or a pathogenic organism specific to a disease, essentially characterized by the following operations: identification of at least one antibody that reacts with the antigen or pathogenic organism specific to the disease; construction of phage libraries which display on the surface of the capsid oligopeptides, expressed from random sequence oligonucleotidic inserts introduced into a gene coding for a phage capsid protein using genetic manipulation techniques (for example using a plasmid engineered for the purposes of the invention, the genetic map of which is shown in the figure); selection of the phages that display on the surfaces of the capsid antigenic oligopeptides recognized by said antibody; optional use of the selected phages and/or fragments thereof and/or their derivatives for the formulation of diagnostic kits for the specific pathogenic agent, or in general for the diseases, including immunological disorders typical of so-called autoimmune diseases, with known or unknown etiology and/or pathogenesis; optional use of the selected phages and/or fragments thereof and/or their derivatives for the formulation of an antagonist ofthe antigen-antibody reactions for treatment of the disease induced by said antigen; optional use of the selected phages and/or fragments thereof and/or their derivatives to induce a tolerance of the phenomena of hypersensitivity and/or allergy to compounds and/or natural or synthetic preparations; optional immunization of an organism by means of the selected phages and/or fragments thereof and/or their derivatives; and optional verification of the presence, in the serum of the immunized organism, of antibodies that recognize the above antigen or organism specific to the disease.

DESCRIPTION

The subject of the present invention is a process for the preparation ofimmunogens or diagnostic reagents that mimic an antigen or a pathogenicorganism specific to a disease, even if this is uncharacterized or evenunknown (thereby including auto-immune diseases whose etiology and/orpathogenesis is known or unknown). This process is based on theexistence and availability of antibodies, both monoclonal or polyclonal,or of serum containing antibodies, which react specifically with theorganism causing the infection.

Antibodies suitable for use in this process can be specific for anyantigen of interest for which an immunogen or diagnostic reagent thatmimes the antigen is sought. The antigen can be a protein or peptidewhether synthetic, derived from a natural source, or producedrecombinantly; carbohydrate; polysaccharide; glycoprotein; hormone;receptor; antibody; virus; substrate; metabolite; transition stateanalog; cofactor; drug; dye; nutrient; growth factor; cellularcomponent; oncogene product; bacteria and their extracellular products;mammalian cells and extracts therefrom including tumor cells, virusinfected cells and normal cells; parasites; protozoa; malarial antigens;helminths; fungi; rickettsia; or an allergen including but not limitedto pollens, dusts, danders or extracts of the same; or a venom, poison,toxin, or toxoid; nucleic acids including DNA; or any other antigenwithout limitation. Antigens of viruses which are suitable for use inthe present invention include antigens from the viruses including butnot limited to polio virus, influenza virus, HIV, HTLL, papilloma virus,adeno virus, parainfluenza virus, measles virus, mumps virus,respiratory syncytial virus, shipping fever virus, Western and Easternencephalomyelitis virus, Japanese B encephalomyelitis virus, Russianspring-summer encephalomyelitis virus, hog cholera virus, hepatitisvirus, pox virus, rabies, virus, distemper virus, herpes virus,cytomegalo virus, foot and mouth disease virus, rhinovirus, Newcastledisease virus, vaccinia virus; and pseudorabies virus. The mime can bean immunogen, a vaccine, an inhibitor or activator, etc. withoutlimitation.

As is known, all vaccines and diagnostic reagents currently on sale orundergoing clinical tests are conventionally obtained by means ofprocesses based on the manipulation, modification and/or adaptation ofpathogenic organisms or components thereof. These methods have givengood results, but are not without problems. The greatest limitationassociated with these methods is connected with the fact that theydepend upon the availability of information and/or material directlyderiving from pathogenic organisms or components thereof.

Previous attempts to overcome the above described limitation have so farfailed for a lack of an efficient and reproducible experimentalprotocol; in particular, these attempts did not provide sufficientinformation in order to identify and characterize immunogenic mimics tobe used for diagnosis and vaccine therapy. It must be emphasized thatthe present invention is focused on the development of a new technologyaimed at overcoming conceptual and technical inadequancies of previouslyproposed protocols.

A key feature of the present invention is a novel strategy for theselection of antigenic and immunogenic mimics, based on the use, asreagents, of serum samples from patients and a counter-selection steputilizing serum samples from healthy individuals.

Use of the process for preparation according to the present inventionallows this limitation to be overcome, furthermore offering additionaladvantages which will be clear from the following description.

The process for the preparation of immunogens or diagnostic reagentsthat mimic an antigen or a pathogenic organism specific to adisease--according to the present invention--is essentiallycharacterized by the following operations:

identification of at least one antibody that reacts with the antigen orpathogenic organism specific to the disease;

construction of phage libraries which display on the surface of thecapsid oligopeptides, expressed from random sequence oligonucleotidicinserts introduced into a gene coding for the phage capsid using geneticmanipulation techniques;

selection of the phages that display on the surfaces of the capsidantigenic oligopeptides with a first pathologic serum, subsequentscreening with additional pathological sera in order to identify phagethat display oligopeptides that react with all or most of the seratested, and counterscreening with a panel of sera from another set ofindividuals taken as a control in order to identify oligopeptides thatdo not react with all or most sera from controlled individuals;

optional use of the selected phages and/or fragments thereof and/ortheir derivatives for the formulation of diagnostic kits for thespecific pathogenic agent, or in general for the diseases, includingimmunological disorders typical of so-called autoimmune diseases, withknown or unknown etiology and/or pathogenesis;

optional use of the selected phages and/or fragments thereof and/ortheir derivatives for the formulation of an antagonist of theantigen-antibody reactions for treatment of the disease induced by saidantigen;

optional use of the selected phages and/or fragments thereof and/ortheir derivatives to induce a tolerance of the phenomena ofhypersensitivity and/or allergy to compounds and/or natural or syntheticpreparations;

optional immunization of an organism by means of the selected phagesand/or fragments thereof and/or their derivatives; and

optional verification of the presence, in the serum of the immunizedorganism, of antibodies that recognize the above antigen or organismspecific to the disease.

The construction of phage libraries, according to the present invention,can be advantageously performed using the filamentous phages M13, F1 andFd, or derivatives thereof. The reasons for this are the following:

filamentous phages are commonly used as molecular vectors in the fieldof molecular biology and genetic engineering. For example, by takingadvantage of their feature to contain a genome with a single DNA helix,they have been particularly used in DNA sequencing experiments, indirect site mutagenesis experiments and for the expression of proteinsand peptides;

the information required and sufficient for encapsidation of a singlechain DNA genome has been well characterized and can be transferred toother molecular vectors;

it has likewise been demonstrated that at least two proteins of thecapsid of filamentous phages can be modified by means of the addition orinsertion of additional amino acid sequences. The resulting phages areencapsidated, maintain their ability to replicate and, in most cases, toinfect bacterial cells. The foreign amino acid sequences are displayedon the surface of the phage, and can be recognized by interaction withantibodies or with other specific molecules according to the case.

The antibodies that can be used in the process for the preparation ofimmunogens and diagnostic reagents according to the present inventioncan be monoclonal antibodies, polyclonal antibodies, or antibodiescontained in sera. The latter form of embodiment is of particularinterest, because it provides for the first time a reproducibleexperimental strategy to identify novel antigenic and immunogenic mimicsin absence of any information on the structure and properties of thenatural and pathological antigen.

The gene coding for the phage capsid, with random sequenceoligonucleotidic inserts, can be the gene coding for the protein VIII ofthe phage capsid or the gene coding for the protein III of said capsid.

The process according to the invention can be applied withoutrestriction to any antibody or organism responsible for illness. Goodresults have been obtained using monoclonal antibodies, or sera specificfor the surface antigen of the human hepatitis B virus (HBsAg).

The antigenic oligopeptides recognized by the antibodies used can beobtained by expression from random sequence oligonucleotidic inserts,using as a vector, for example, the plasmid pC89.

In the process for the preparation of immunogens and diagnostic reagentsaccording to the present invention, it is possible to select phagescontaining in their capsid from the site identifying the restrictionenzyme EcoRI (GAATTC) to that identifying the restriction enzyme BamHI(GGATCC), one of the aminoacidic sequences SEQ ID NO: 1, SEQ ID NO: 2,SEQ ID NO: 3, SEQ ID NO:7 and SEQ ID NO: 9 to 47.

The present invention is not limited to the process for the preparationof immunogens or diagnostic reagents against a specific pathogenicagent, but also extends to the immunogens and diagnostic reagentsobtainable using the process illustrated above, and to the phages usablein the process mentioned above.

Furthermore, the invention also extends to the plasmids pC89 containing,wholely or in part, a nucleotidic sequence chosen from the groupcomprising the sequences SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 andSEQ ID NO:8.

The present invention refers also to oligopeptides obtainable by theabove process which react with pathological sera from individualsaffected by the same disease affecting the patients whose sera have beenused for the selection and screening of phage displaying saidoligopeptides and which do not react with sera from individual notaffected by the same disease. The above oligopeptides are capable ofeliciting in a living organism an immune response against the naturalantigens or antibodies against HCV or antibodies against HBV.

Subject matter of the present invention is also the use of the aboveoligopeptides as immunogens to elicit an antibody response againstspecific pathological antigens, such as for instance infectiouspathogens, in the case said elicited antibodies also being protective orneutralizing, to formulate a vaccine against said pathogenic agents.

The immunogens obtained from the process of the present invention areuseful as vaccines or immunizing agents as well as being useful asdiagnostic reagents. The vaccines or immunizing agents are administeredto a patient in need of such treatment according to standard methodsknown in the art. The vaccine or immunizing agents can be administeredand used either singly or in combination. The vaccines and immunogens ofthe present invention can comprise the phage or protein and peptidesisolated therefrom.

Kits containing the immunogens obtained from the process of the presentinvention may be prepared. Such kits are used to detect the presence ofthe antigen in a sample. Such characterization is useful for a varietyof purposes including but not limited to forensic analyses andepidemiological studies. Such a kit would comprise a compartmentalizedcarrier suitable to hold in close confinement at least one container.The carrier would further comprise reagents such as the immunogens, andantibodies suitable for detecting the antigens. The carrier may alsocontain a means for detection such as labeled antigen or enzymesubstrates or the like.

Pharmaceutically useful compositions comprising the immunogens andvaccines of the present invention, may be formulated according to knownmethods such as by the admixture of a pharmaceutically acceptablecarrier. Examples of such carriers and methods of formulation may befound in Remington's Pharmaceutical Sciences. To form a pharmaceuticallyacceptable compositions suitable for effective administration, suchcompositions will contain an effective amount of the vaccine orimmunogen of the present invention.

Therapeutic or diagnostic compositions of the invention are administeredto an individual in amounts sufficient to treat or diagnose the relevantdisorders. The effective amount may vary according to a variety offactors such as the individual's condition, weight, sex and age. Otherfactors include the mode of administration. The pharmaceuticalcompositions may be provided to the individual by a variety of routessuch as subcutaneous, topical, oral and intramuscular.

The present invention also has the objective of providing suitabletopical, oral systemic and parenteral pharmaceutical formulations foruse in the novel methods of treatment of the present invention. Thecompositions containing vaccine or immunogens identified according tothis invention as the active ingredient can be administered in a widevariety of therapeutic dosage forms in conventional vehicles foradministration. For example, the vaccines and immunogens can beadministered in such oral dosage forms as tablets, capsules (eachincluding timed release and sustained release formulations), pills,powders, granules, elixirs, tinctures, solutions, suspensions, syrupsand emulsions, or by injection. Likewise, they may also be administeredin intravenous (both bolus and infusion), intraderitoneal, subcutaneous,topical with or without occlusion, or intramuscular form, all usingforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the vaccines and immunogens can beemployed.

The daily dosage of the vaccines and immunogens may be varied over awide range from 0.01 to 1000 mg per adult human/per day. For oraladministration, the vaccines and immunogens are preferably provided inthe form of scored or unscored tablets containing 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. An effective amount of the vaccines and immunogens isordinarily supplied at a dosage level of from about 0.0001 mg/kg toabout 100 mg/kg of body weight per day. The range is more particularlyfrom about 0.001 mg/kg to 10 mg/kg of body weight per day. The dosagesof the vaccines and immunogens are adjusted when combined to achievedesired effects. On the other hand, dosages of these various agents maybe independently optimized and combined to achieve a synergistic resultwherein the pathology is reduced more than it would be if either agentwere used alone.

Advantageously, vaccine or immunogens of the present invention may beadministered in a single dose, or a single daily dose, or the totaldaily dosage may be administered in divided doses of two, three or fourtimes daily. Furthermore, vaccine or immunogens for the presentinvention can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin that art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

For combination treatment with more than one active agent, where theactive agents are in separate dosage formulations, the active agents canbe administered concurrently, or they each can be administered atseparately staggered times.

The dosage regimen utilizing the vaccine or immunogens of the presentinvention is selected in accordance with a variety of factors includingtype, species, age, weight, sex and medical condition of the patient;the severity of the condition to be treated; the route ofadministration; the renal and hepatic function of the patient; and theparticular vaccine or immunogen thereof employed. A physician orveterinarian of ordinary skill can readily determine and prescribe theeffective amount of the vaccine or immunogens of the present inventionrequired to prevent, counter or arrest the progress of the condition.Optimal precision in achieving concentrations of the vaccine orimmunogens of the present invention within the range that yieldsefficacy without toxicity requires a regimen based on the kinetics ofthe vaccine or immunogens of the present invention availibility totarget sites. This involves a consideration of the distribution,equilibrium, and elimination of the vaccine or immunogens of the presentinvention.

In the methods of the present invention, the vaccine or immunogensherein described in detail can form the active ingredient, and aretypically administered in admixture with suitable pharmaceuticaldiluents, excipients or carriers (collectively referred to herein as"carrier" materials) suitably selected with respect to the intended formof administration, that is, oral tablets, capsules, elixirs, syrups andthe like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active vaccine or immunogen component can be combined withan oral, non-toxic pharmaceutically acceptable inert carrier such asethanol, glycerol, water and the like. Moreover, when desired ornecessary, suitable binders, lubricants, disintegrating agents andcoloring agents can also be incorporated into the mixture. Suitablebinders include, without limitation, starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include, without limitation,sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride and the like. Disintegrators include,without limitation, starch, methylcellulose, agar bentonite, xanthan gumand the like.

For liquid forms the active vaccine or immunogen component can becombined in suitably flavored suspending or dispersing agents such asthe synthetic and natural gums, for example, tragacanth, acacia,methylcellulose and the like. Other dispersing agents which may beemployed include glycerin and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

Topical preparations containing the active vaccine or immunogencomponent can be admixed with a variety of carrier materials well knownin the art, such as, e.g. alcohols, aloe vera gel, allantoin, glycerine,vitamin A and E oils, mineral oil,PPG2 myristyl propionate, and the liketo form,e.g. alcoholic solutions, topical cleansers, cleansing creams,skin gels, skin lotions, and shampoos in cream or gel formulations.

The vaccine or immunogens of the present invention can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine or phosphatidylcholines.

Vaccine or immunogens of the present invention may also be delivered bythe use of monoclonal antibodies as individual carriers to which thevaccine or immunogen molecules are coupled. The vaccine or immunogens ofthe present invention may also be coupled with soluble polymers astargetable vaccine or immunogen carriers. Such polymers can includepolyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacryl-amidephenol,polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidemolylysinesubstituted with palmitoyl residues. Furthermore, the vaccine orimmunogens of the present invention may be coupled to a class ofbiodegradable polymers useful in achieving controlled release of avaccine or immunogen, for example, polyactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Up to this point a general description has been given of the subjects ofthe present invention. With the assistance of the following examples, amore detailed description will now be given of specific embodiments ofthe invention, aimed at giving a better understanding of the objects,characteristics, advantages and methods of application thereof. Thefollowing examples refer, respectively, to embodiments of the processfor the preparation of immunogens and diagnostic reagents against aspecific pathogenic agent, according to the present invention; to ademonstration of the effectiveness of the clones selected forpreparation of immunogens based on the effects produced by samples ofserum from test animals immunized using the single clones; and to ademonstration of the effectiveness of the clones selected forpreparation of diagnostic reagents, based on their specific reactionwith the serum of individuals immunized with HBsAg.

The single FIGURE enclosed shows a portion of the genetic map of theplasmid pC89 engineered for the purposes of the invention. Thenucleotidic sequence for the restriction sites and the correspondingaminoacidic sequence are illustrated below the portion of the abovementioned genetic map. The wild-type aminoacidic sequence of theamino-terminal end of mature pVIII has been modified in order tointroduce single EcoRI and BamHI sites.

EXAMPLE 1

Process for the Preparation of Specific Diagnostic Reagents andImmunogens for the Disease Caused by the Human Hepatitis B Virus (HBV)

The following process was used according to the invention:

A first "library" of epitopes was prepared, made up of phages havingoligopeptides with 9 amino acids displayed on the surface of the capsid,expressed by random sequence oligonucleotidic inserts introduced intothe gene coding for the protein VIII of the phage capsid. For expressionof the recombinant proteins containing the epitope, the plasmid pC89 wasused, engineered as described in F. Felici et al., Selection of AntibodyLigands from a Large Library of oligopeptides Expressed on a MultivalentExposition Vector, J. Mol. Biol. (1991), 222, 301-310, of which aportion of the genetic map is shown in the FIGURE.

A second epitope "library" was prepared in the same way as the first,with the difference that two cysteine residues are present at the twoends of the insert, as described in A. Luzzago et al., Mimicking ofdiscontinuous epitopes by phage displayed peptides, I. Epitope mappingof human H Ferritin using a phage library of contrained peptides, Gene(1993), 128, 51-57.

A sample of sera from individuals immunized using a recombinant form ofthe HBV surface antigen (HBsAg) was tested for the presence of specificantibodies against HBsAg. The sera with a high antibody content againstHBsAg were then used.

The antibodies contained in these sera were immobilized on a solidmatrix and incubated with the phage libraries. The phages specificallyretained by these antibodies were then eluted and amplified.

Bacteria infected by the phages selected as above were plated on a solidculture medium and transferred onto nitrocellulose filters.Subsequently, these filters were incubated with sera from individualsimmunized against HBsAg different from the serum used for the firstenrichment. The phages specifically recognized by antibodies present inthese sera were identified and isolated.

The phages identified as above were counter-selected for reactivity toantibodies present in the sera of individuals not immune to HBsAg, usingthe ELISA test.

The phages resulting from this counter-selection were checked forspecificity of reaction to anti-HBsAg antibodies by means of competitionin the ELISA test.

The nucleotidic sequence coding for the epitopes identified in thismanner was subsequently determined (SEQ ID NO: 4, 5, 6, 8).

EXAMPLE 2

Demonstration of the Effectiveness of the Selected Phases as SpecificImmunogens for the Disease Caused by the Human Hepatitis Virus (HBV)

The following process was used:

The phages, selected as described above, were amplified and purified.

The purified phages were injected into test animals (mice, rats andrabbits), according to the process described by V. F. de la Cruz et al.,Immunogenicity and Epitope Mapping of Foreign Sequences via GeneticallyEngineered Filamentous Phage, J. Biol. Chem. (1988) 263, 9, 4318-4322,and by J. Greenwood et al., Multiple Display of Foreign Peptides on aFilamentous Bacteriophage, J. Mol. Biol. (1991) 220, 821-827.

The sera of animals immunized as above were tested for the presence ofantibodies capable of interacting with HBsAg, using the ELISA test. Thismethod underlined the presence of a high level of anti-HBsAg antibodiesin the serum of test animals immunized as above.

The same immunization process was adopted, using as immunogens syntheticoligopeptides reproducing the amino acid sequence (SEQ ID from NO: 1 toNO: 3 and NO:7) of the epitopes identified according to the proceduregiven above. This method underlined the presence of a high level ofanti-HBsAg antibodies in the serum of test animals immunized as above.

The same immunization process was adopted, using as immunogensrecombinant forms produced in bacteria of the heavy chain of humanferritin displaying on their surface the synthetic oligopeptidesreproducing the amino acid sequence of the epitopes identified accordingto the procedure given above. This method underlined the presence of ahigh level of anti-HBsAg antibodies in the serum of test animalsimmunized as above.

EXAMPLE 3

Demonstration of the Effectiveness of the Selected Phases as DiagnosticReagents for Determination of the Presence of Anti-HBsAg Antibodies inSerum

A process comprising the following operations was used:

20 human sera from individuals vaccinated against HBsAg were analyzed inan ELISA test for their ability to recognize specifically the phageclones, identified as described in example 1, showing the peptidesequences described (SEQ ID from NO: 1 to NO: 3 and NO: 7). The resultsshow that 80% of the sera specifically recognize at least one of thefour sequences selected.

16 human serums from patients suffering from hepatitis B and containinganti-HBsAg antibodies were analyzed in an ELISA test for their abilityto recognize specifically the phage clones, identified as described inexample 1, showing the peptide sequences described (SEQ ID from NO: 1 toNO: 3 and NO:7). The results show that 44% of the sera specificallyrecognize at least one of the four sequences selected.

20 human sera from individuals not vaccinated against HBsAg wereanalyzed in an ELISA test for their ability to recognize specificallythe phage clones, identified as described in example 1, displaying thepeptide sequences described (SEQ ID from NO: 1 to NO:3 and NO:7). Theresults show that none of the sera specifically recognize any of thefour sequences selected.

EXAMPLE 4

Process for the Preparation of Specific Diagnostic Reagents andImmunogens for the Disease Caused by the Human Hepatitis C Virus (HCV)

The following process was used according to the invention:

A first "library" of epitopes was prepared, made up of phages havingoligopeptides with 9 amino acids displayed on the surface of the capsid,expressed by random sequence oligonucleotidic inserts introduced intothe gene coding for the protein VIII of the phage capsid. For theexpression of the recombinant proteins containing the epitope, theplasmid pCS89 was used, engineered as described in F. Felici et al.,Selection of Antibody Ligands from a Large Library of oligopeptidesExpressed on a Multivalent Exposition Vector, J. Mol. Biol. (1991), 222,301-310, of which a portion of the genetic map is shown in the FIGURE.

A second epitope "library" was prepared in the same way as the first,with the difference that two cysteine residues are present at the twoends of the insert, as described in A. Luzzago et al., Mimicking ofdiscontinuous epitopes by phage displayed peptides, I. Epitope mappingof human H Ferritin using a phage library of contrained peptides, Gene(1993), 128, 51-57.

Sera from patients clinically characterized by being infected with thehepatitis C virus were then used.

The antibodies contained in these sera were immobilized on a solidmatrix and incubated with the phage libraries. The phages specificallyretained by these antibodies were then eluted and amplified.

Bacteria infected by the phages selected as above were plated on a solidculture medium and transferred onto nitrocellulose filters.Subsequently, these filters were incubated with serums from patientsinfected with HCV, different from the serum used for the initialenrichment. The phages specifically recognized by antibodies present inthese sera were identified and isolated.

The phages identified as above were counter-selected for reactivity toantibodies present in the sera of individuals not infected with HCV,using the ELISA test.

The reaction specificity of the above phages with anti-HCV antibodies isevaluated statistically as follows. The frequency with which asignificant number of sera from patients infected with HCV recognize thephage clones is determined in an ELISA test. In parallel, again usingthe ELISA test, absence of recognition of the same phage clones by asignificant number of sera from individuals not infected with HCV istested. For each phage clone, the specificity is evaluated by comparisonof the frequence of recognition by sera from patients infected with HCVwith that of sera from non-infected individuals.

The epitope peptidic sequence identified in this manner was subsequentlydetermined (SEQ ID from NO: 9 to NO: 30).

EXAMPLE 5

Demonstration of the Effectiveness of the Selected Phages as DiagnosticReagents for Determination of the Presence of Anti-HCV Antibodies inSerum

A process comprising the following operations was used:

40 human sera from individuals not infected with HCV were analyzed in anELISA test for their ability to recognize specifically the phage clones,identified as described in example 4, displaying the peptide sequencesdescribed (SEQ ID from NO: 9 to NO: 23). The results show that none ofthe sera recognizes the sequences selected.

42 human sera from patients infected with HCV were analyzed in an ELISAtest for their ability to recognize specifically the phage clones,identified as described in example 4, displaying the peptide sequencesdescribed (SEQ ID from NO: 9 to NO: 23). The results show that eachphage clone is recognized specifically by the sera selected, with afrequency varying from 15 to 65% (see table I). The same results alsoshow that each of the 42 sera tested specifically recognizes at leastone of the sequences selected.

The sequences selected give an effective indication of the presence ofanti-HCV antibodies in the blood of all patients examined, and do notreact with blood from non-infected individuals. These data show that thegroup of phage clones selected forms a reliable system for the diagnosisof infection by the hepatitis C virus.

                                      TABLE 1                                     __________________________________________________________________________      #STR1##                                                                      ##STR2##                                                                     __________________________________________________________________________

EXAMPLE 6

Process for the Preparation of Specific Diagnostic Reagents andImmunogens for the Disease Type II Cryoglobulinemia Caused by and/orAssociated with the Human Hepatitis C Virus (HCV)

The following process was used according to the invention:

A first "library" of epitopes was prepared, made up of phages displayingoligopeptides with 9 amino acids on the surface of the capsid, expressedby random sequence oligonucleotidic inserts introduced into the genecoding for the protein VIII of the phage capsid. For expression of therecombinant proteins containing the epitope, the plasmid pC89 was used,engineered as described in F. Felici et al., Selection of AntibodyLigands from a Large Library of Oligopeptides Expressed on a MultivalentExposition Vector, J. Mol. Biol. (1991), 222, 301-310, of which aportion of the genetic map is shown in the FIGURE.

A second epitope "library" was prepared in the same way as the first,with the difference that two cysteine residues are present at the twoends of the insert, as described in A. Luzzago et al., Mimicking ofdiscontinuous epitopes by phage displayed peptides, I. Epitope mappingof human H Ferritin using a phage library of contrained peptides, Gene(1993), 128, 51-57.

Samples of antibodies from individuals suffering from type IICryoglobulinemia caused by and/or associated with the human hepatitis Cvirus (HCV) were immobilized on a solid matrix and incubated with thephage libraries. The phages specifically retained by said antibody werethen eluted and amplified.

Bacteria infected by the phages selected as above were plated on a solidculture medium and transferred onto nitrocellulose filters.Subsequently, these filters were incubated with sera from patientssuffering from type II Cryoglobulinemia caused by and/or associated withhuman hepatitis C virus (HCV), different from the serum used for thefirst enrichment. The phages specifically recognized by antibodiespresent in these serums were identified and isolated.

The phages identified as above were counter-selected for reactivity toantibodies present in the serums of individuals not infected with typeII Cryoglobulinemia caused by and/or associated with human hepatitis Cvirus (HCV), using the ELISA test.

The reaction specificity of the phages resulting from thiscounter-selection with antibodies specific for Type II Cryoglobulinemiacaused by and/or associated with the human hepatitis C virus isevaluated statistically as follows. The frequency with which asignificant number of sera from patients suffering from type IICryoglobulinemia caused by and/or associated with the human hepatitis Cvirus (HCV) recognize the phage clones is determined in an ELISA test.In parallel, again using the ELISA test, absence of recognition of thesame phage clones by a significant number of sera from individuals notsuffering from the disease is tested. For each phage clone, thespecificity is evaluated by comparison of the frequency of recognitionby sera from patients suffering from the disease with that of sera fromhealthy individuals.

The epitope peptidic sequence identified in this manner was subsequentlydetermined (SEQ ID from NO: 31 to NO: 42).

EXAMPLE 7

Demonstration of the Effectiveness of the Selected Phages as DiagnosticReagents for Determination of the Presence in the Serum of AntibodiesSpecific for the Disease Type II Cryoglobulinemia Caused by and/orAssociated with the Human Hepatitis C Virus (HCV)

A process comprising the following operations was used:

16 human sera from individuals not suffering from type IICryoglobulinemia, caused by and/or associated with the human hepatitis Cvirus (HCV), were analyzed in an ELISA test for their ability torecognize specifically the phage clones, identified as described inexample 6, showing the peptide sequences described (SEQ ID from NO: 31to NO: 42). The results show that none of the serums recognizes thesequences selected.

80 human sera from patients suffering from type II Cryoglobulinemia,caused by and/or associated with the human hepatitis C virus (HCV), wereanalyzed in an ELISA test for their ability to recognize specificallythe phage clones, identified as described in example 6, displaying thepeptide sequences described (SEQ ID from NO: 31 to NO: 42). The resultsshow that each phage clone is recognized specifically by the seraselected, with a frequency varying from 15 to 60%.

The sequences selected give an effective indication of the presence ofantibodies specific for type II Cryoglobulinemia, caused by and/orassociated with the human hepatitis C virus (HCV), in the blood of allpatients examined, and do not react with blood from individuals notsuffering from the disease. These data show that the group of phageclones selected forms a reliable system for diagnosis of the diseasetype II Cryoglobulinemia caused by and/or associated with the humanhepatitis C virus (HCV).

The sequences selected show significant homology with the human LAG-3gene sequence, which is specifically expressed by T lymphocytes and"natural killer" cells. The same antibodies used to select the phageclones react with the portion of the protein LAG-3 that is homologouswith the sequence of the selected phage clones. This recognition can beabolished by competition with the selected phage clones. These resultsindicate that the selected phage clones can be used to block theautoantibody binding to the protein LAG-3.

EXAMPLE 8

Process for the Preparation of Diagnostic Reagents for Type I DiabetesAutoimmune Disease and Demonstration of the Effectiveness of theSelected Phages as Diagnostic Reagents for Determination of the Presencein the Blood of Autoantibodies Characterization Autoimmune Diseases

The following process was used according to the invention:

A first "library" of epitopes was prepared, made up of phages havingoligopeptides with 9 amino acids displayed on the surface of the capsid,expressed by random sequence oligonucleotidic inserts introduced intothe gene coding for the protein VIII of the phage capsid. For expressionof the recombinant proteins containing the epitope, the plasmid pC89 wasused, engineered as described in F. Felici et al., Selection of AntibodyLigands from a Large Library of Oligopeptides Expressed on a MultivalentExposition Vector, J. Mol. Biol. (1991), 222, 301-310.

A second epitope "library" was prepared in the same way as the first,with the difference that two cysteine residues are present at the twoends of the insert, as described in A. Luzzago et al., Mimicking ofdiscontinuous epitopes by phage displayed peptides, I. Epitope mappingof human H. Ferritin using a phage library of constrained peptides, Gene(1993), 128, 51-57.

A sample of sera from diabetic patients at the beginning of their type Idiabetes clinical history was tested for the presence of antibodiesspecific for certain known markers characteristic of the disease, suchas anti-insulin and ICA antibodies, or antibodies against the pancreaticislets. A serum with a high antibody content was then used forselection.

The antibodies contained in this serum were immobilized on a solidmatrix and incubated with the phage libraries. The phages specificallyretained by these antibodies were then eluted and amplified.

Bacteria infected by the phages selected as above were plated on a solidculture medium and transferred onto nitrocellulose filters.Subsequently, these filters were incubated with sera from diabeticindividuals different from the serum used for the first enrichment. Thephages specifically recognized by antibodies present in these sera wereidentified and isolated.

The phages identified as above were counter-selected for reactivity toantibodies present in the sera of individuals not suffering from type Idiabetes, using the ELISA test.

The phages resulting from this counter-selection were checked forspecificity of reaction by means of large scale screening using serafrom diabetic patients at different stages of the disease. Thenucleotidic sequence coding for the epitopes identified in this mannerwas then determined.

The phage clones were analyzed using the following process:

25 human sera taken from individuals at the time of the first clinicalappearance of type I diabetes were analyzed using an ELISA test fortheir ability to recognize specifically the phage clones, identified asdescribed and displaying the peptide sequences described (SEQ ID NO: 43,SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47). The resultsshow that 36% of the sera recognized specifically at least one of the 5sequences selected.

16 human sera taken from individuals with autoimmune pathologies otherthan diabetes were analyzed using an ELISA test for their ability torecognize specifically the phage clones, identified as described inexample 8, and displaying the peptide sequences described (SEQ ID NO:43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47). Theresults show that 18% of the sera recognized specifically at least oneof the 5 sequences selected.

50 human sera taken from individuals not suffering from diabetes or fromother autoimmune pathologies were analyzed using an ELISA test for theirability to recognize specifically the phage clones, identified asdescribed in example 8, and displaying the peptide sequences described(SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46; SEQ ID NO:47). The results show that none of the sera recognized specifically anyof the 5 sequences selected.

EXAMPLE 9

Process for the Preparation of Diagnostic Reagents and ImmunogensSpecific for Detection and Induction of the Immune Response of the HumanTumoral Protein NEU (p185^(HER2))

The following process was used according to the invention:

The monoclonal antibodies MGr2 and MGr6 were identified as recognizingspecifically the human tumoral protein NEU (p185^(HER2)).

Two epitope "libraries" were prepared, made up of phages displayingoligopeptides on the surface of the capsid (as described in example 1),which were then examined using the biopanning method (V. Parmley, S. F.& Smith, G. P., Antibody-selectable filamentous fd phage vectors:affinity purification of target genes, Gene (1988) 73, 305-318) toselect the clones that react specifically with the above mentionedantibodies.

Bacteria infected by the phages selected as above were plated on a solidculture medium and transferred onto nitrocellulose filters.Subsequently, these filters were incubated with the monoclonalantibodies MGr2 and MGr6. The reaction specificity of the phagesidentified in this way was controlled using the ELISA test.

The peptidic sequence of the epitopes identified as above wassubsequently determined by means of analysis of the correspondingnucleotidic coding sequence (for MGr2 SEQ ID from NO: 48 to NO: 56, forMGr6 SEQ ID from NO: 57 to NO: 68).

The phages, selected as above, were amplified, purified and injectedinto test animals according to the procedure described in Example 2. Theserum from animals immunized in this manner was tested for the presenceof antibodies capable of interacting with NEU, using theimmunohistochemical test.

This method underlined the presence of a significant level of anti-NEUantibodies in the blood of test animals immunized in this manner.

The results obtained with the phages described in this exampledemonstrate the effectiveness of said phages as antigenic andimmunogenic substitutes of the human tumoral protein NEU. This may allowthe phages thus obtained, or derivatives thereof, to be used as reagentsfor the detection of anti-NEU antibodies in sera from patients sufferingfrom tumors and/or as specific immunogens to stimulate an anti-NEUantibody response.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                  - -  - - (1) GENERAL INFORMATION:                                             - -    (iii) NUMBER OF SEQUENCES: 68                                          - -  - - (2) INFORMATION FOR SEQ ID NO: 1:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #1:                           - - Glu Phe Cys Arg Thr Cys Ala His Pro Gly Gl - #u His Ala Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 2:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acid                                                  (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #2:                           - - Glu Phe Cys Gly Pro Phe Tyr Leu Ser Ala Pr - #o Gln Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 3:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #3:                           - - Glu Phe Cys Gly Pro Phe Phe Leu Ala Ala Se - #r Val Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 4:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 47 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA                                               - -    (iii) HYPOTHETICAL: no                                                 - -     (iv) ANTI-SENSE: no                                                   - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polynucleoti - #de                                              (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #4:                           - - GAATTCTGCC GAACCTGCGC CCATCCAGGT GAGCATGCGG GGGATCC   - #                    47                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO: 5:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 47 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA                                               - -    (iii) HYPOTHETICAL: no                                                 - -     (iv) ANTI-SENSE: no                                                   - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polynucleoti - #de                                              (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #5:                           - - GAATTCTGCG GGCCTTTTTA TCTCTCTGCA CCTCAGTGCG GGGATCC   - #                    47                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO: 6:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 47 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA                                               - -    (iii) HYPOTHETICAL: no                                                 - -     (iv) ANTI-SENSE: no                                                   - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polynucleoti - #de                                              (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #6:                           - - GAATTCTGCG GTCCCTTCTT TCTCGCGGCT TCCGTATGCG GGGATCC   - #                    47                                                                        - -  - - (2) INFORMATION FOR SEQ ID NO: 7:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #7:                           - - Glu Phe Cys Gly Pro Phe Phe Leu Ser Pro Th - #r Ser Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 8:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 47 base - #pairs                                                  (B) TYPE: nucleic acid                                                        (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: DNA                                               - -    (iii) HYPOTHETICAL: no                                                 - -     (iv) ANTI-SENSE: no                                                   - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polynucleoti - #de                                              (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #8:                           - - GAATTCTGCG GTCCGTTTTT TCTCTCCCCG ACGTCATGCG GGGATCC  4 - #7              - -  - - (2) INFORMATION FOR SEQ ID NO: 9:                                    - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #9:                           - - Glu Phe Cys Leu Pro Ala His Gly Pro Ser Le - #u Ser Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 10:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #10:                          - - Glu Phe Cys Leu Pro Trp Gly Val Ala Ala Ar - #g Arg Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 11:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #11:                          - - Glu Phe Cys Pro Thr His Tyr Thr Thr Ser Al - #a Pro Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 12:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #12:                          - - Glu Phe Cys Pro Thr His Tyr Ile Ser Ser Ar - #g His Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 13:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #13:                          - - Glu Phe Cys Pro Thr His Tyr Ile Ser Thr Se - #r Leu Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 14:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #14:                          - - Glu Phe Cys Thr Arg His Tyr Leu Arg Pro Gl - #y Leu Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 15:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #15:                          - - Glu Phe Cys Pro Ser His Tyr Val Pro Arg Il - #e Tyr Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 16:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #16:                          - - Glu Phe Cys Pro Pro His Leu Thr Leu Ser Se - #r Cys Arg Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 17:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #17:                          - - Glu Phe Cys Lys Leu Asn Ser Arg Gly Ser Il - #e Ser Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 18:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #18:                          - - Glu Phe Cys Gly Lys Phe Pro Gly Ser Lys Pr - #o Ser Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 19:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #19:                          - - Glu Phe Cys Phe Pro Gly Gly Pro Pro Leu Ar - #g Ala Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 20:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #20:                          - - Glu Phe Cys Ala Pro Ser Leu Pro Ala Gly Ty - #r Leu Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 21:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #21:                          - - Glu Phe Cys Gln Val Pro Gln Ser Arg Leu Gl - #u Pro Trp Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 22:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #22:                          - - Glu Phe Asn Lys Arg Glu Trp Ala Pro Pro Pr - #o Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 23:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #23:                          - - Glu Phe Asn Lys Thr Lys Gln Asn Pro Asn Le - #u Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 24:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #24:                          - - Glu Phe Thr Ser Leu Gln Pro Asp Arg Ala Gl - #n Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 25:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #25:                          - - Glu Phe Ser Gly Leu Arg Pro Gly Lys Phe Gl - #n Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 26:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #26:                          - - Glu Phe Thr Gly Val Arg Glu Ile Ser Phe Gl - #y Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 27:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #27:                          - - Glu Phe Thr Gly Leu Arg Glu Ser Pro Ser Me - #t Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 28:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #28:                          - - Glu Phe Ser His Pro His Phe Ser Gly Leu Gl - #u Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 29:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #29:                          - - Glu Phe Thr Gly Leu Arg Ser Arg Tyr Pro Al - #a Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 30:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 12 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #30:                          - - Glu Phe Thr Gly Leu Arg His Lys Thr Ser Al - #a Asp                      1               5   - #                10  - #    12                           - -  - - (2) INFORMATION FOR SEQ ID NO: 31:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific            antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #31:                          - - Glu Phe Cys His Pro Leu Ala Pro Ala Gly Th - #r Phe Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 32:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 14 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with                                      specific - #antibodies                                          - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #32:                          - - Glu Phe Cys His Pro Leu Ala Pro Leu Asn Ph - #e Cys Gly Asp              1               5   - #                10  - #            14                   - -  - - (2) INFORMATION FOR SEQ ID NO: 33:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with                                      specific - #antibodies                                          - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #33:                          - - Glu Phe Cys Gly His Pro Leu Ala Pro Pro Gl - #n Ala Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 34:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #34:                          - - Glu Phe Cys His Pro Leu Ser Pro Arg Pro Le - #u Gln Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 35:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #35:                          - - Glu Phe Cys His Pro Leu Ala Pro Pro His Pr - #o Ser Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 36:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #36:                          - - Glu Phe Cys His Pro Leu Ser Pro His Pro Se - #r Tyr Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 37:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #37:                          - - Glu Phe Cys His Pro Leu Ala Thr Gly Pro Hi - #s Leu Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 38:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #38:                          - - Glu Phe Cys His Pro Leu Ala Pro Ser Pro Al - #a Val Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 39:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #39:                          - - Glu Phe Cys His Pro Leu Pro Pro Ala Ala Th - #r Phe Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 40:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #40:                          - - Glu Phe Cys His Pro Leu Ala Pro Val Pro Ar - #g Gln Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 41:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #41:                          - - Glu Phe Cys His Pro Leu Ser Pro Ser Pro Ty - #r Met Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 42:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #42:                          - - Glu Phe Cys Asn His Pro Leu Ser Pro Ser Gl - #y Ala Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 43:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #43:                          - - Glu Phe Cys His Ala Val Lys Gly Phe Ser Al - #a Val Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 44:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #44:                          - - Glu Phe Cys His Ala Val Lys Val Gly Asn Pr - #o Ser Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 45:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #45:                          - - Glu Phe Cys His Ala Thr Lys Thr Pro Trp Th - #r Thr Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 46:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #46:                          - - Glu Phe Cys Arg Ala Pro Ser Gly Val Ile Va - #l Gln Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 47:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: recombinant protein                               - -    (iii) HYPOTHETICAL: yes                                                - -      (v) FRAGMENT TYPE: internal                                          - -    (vii) IMMEDIATE SOURCE:                                                         (A) LIBRARY: of recombi - #nant peptides on phage                             (B) CLONE: phagic                                                    - -     (ix) FEATURE:                                                                  (A) NAME/KEY: polypeptide                                                     (B) IDENTIFICATION METHOD: - # selection with specific             antibodies                                                                       - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #47:                          - - Glu Phe Cys Gly Gly Ala Ser Ser Gly Cys Ly - #s Pro Cys Gly Asp         1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 48:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #48:                          - - Gly Glu Phe Tyr Thr Pro Thr Trp Met Leu Pr - #o Glu Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 49:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #49:                          - - Gly Glu Phe Ser Pro Pro Trp Met Leu Pro Se - #r Val Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 50:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #50:                          - - Gly Glu Phe Thr Pro Asn Trp Met Leu Gln As - #n Leu Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 51:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #51:                          - - Gly Glu Phe Thr Pro Arg Trp Met Leu Ser Ar - #g Glu Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 52:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #52:                          - - Gly Glu Phe Thr Pro Thr Trp Met Leu Ala Ar - #g Trp Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 53:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #53:                          - - Glu Phe Cys Gly Pro Leu Asp Ser Leu Phe Al - #a Gln Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 54:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #54:                          - - Glu Phe Cys Gly Pro Ile Ser Ala Leu Phe Al - #a Ser Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 55:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #55:                          - - Glu Phe Cys Gly Pro Ile His Ala Leu Phe Le - #u Asp Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 56:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #56:                          - - Glu Phe Cys Gly Pro Ile Ser Ser Leu Phe Gl - #y Asp Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 57:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #57:                          - - Gly Glu Phe Ile Cys His Ser Asp Cys Ala Al - #a Gly Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 58:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #58:                          - - Gly Glu Phe Ile Cys His Ser Asp Cys Ala Se - #r Gly Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 59:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #59:                          - - Gly Glu Phe Ile Ala Cys His Ser Asp Cys Gl - #y Ser Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 60:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #60:                          - - Gly Glu Phe Trp Thr Pro Leu Lys Cys Asp Al - #a Leu Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 61:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #61:                          - - Gly Glu Phe Pro Ala Ala Phe Gly Lys Leu Gl - #y Val Asp Pro Lys          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 62:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #62:                          - - Glu Phe Cys Leu Val Leu Pro Lys Val Lys Me - #t Ala Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 63:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #63:                          - - Glu Phe Cys Ala Arg Leu Pro Val Leu Lys Le - #u Val Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 64:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #64:                          - - Glu Phe Cys Ile Trp Leu Pro Arg Ile Lys Le - #u Ser Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 65:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #65:                          - - Glu Phe Cys Phe Ser Ile Pro Ser Leu Lys Th - #r Val Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 66:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #66:                          - - Glu Phe Cys Phe Arg Gly Pro Arg Gln Lys Le - #u Tyr Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 67:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #67:                          - - Glu Phe Cys Leu Pro Leu Leu Gly Arg Lys Th - #r Met Cys Gly Asp          1               5   - #                10  - #                15               - -  - - (2) INFORMATION FOR SEQ ID NO: 68:                                   - -      (i) SEQUENCE CHARACTERISTICS:                                                 (A) LENGTH: 15 amino - #acids                                                 (B) TYPE: amino acid                                                          (C) STRANDEDNESS: single                                                      (D) TOPOLOGY: linear                                                 - -     (ii) MOLECULE TYPE: protein                                           - -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO: - #68:                          - - Glu Phe Cys Trp Ile His His Leu Leu Lys Va - #l Val Cys Gly Asp          1               5   - #                10  - #                15             __________________________________________________________________________

We claim:
 1. A process for preparation of a peptide that mimics anantigen or a pathogenic organism specific to a disease, comprising thesteps of:(a) collecting serum samples from at least two patients whosesera contain antibodies to the antigen or pathogenic organism and fromat least one control individual whose serum would not be expected tocontain antibodies to the antigen or pathogenic organism; (b) contactingthe antibodies from the serum sample from said first patient with aphage-displayed random peptide library and selecting a first pool ofphages which are bound by antibodies present in the serum sample fromsaid first patient; (c) contacting the phages in said first pool ofphages with the antibodies from a serum sample from said second patientand selecting a second group of phages that are bound by antibodiespresent in samples from both said first patient and from said secondpatient; (d) contacting phages from the second group with serum fromsaid control individual to identify phages that are not bound byantibodies contained in the sera from said control individual; and (e)if a phage is bound by antibodies in the sera from at least both saidfirst and second patients but is not bound by antibodies contained inthe serum from said control individual, identifying and producing thepeptide displayed by said phage.
 2. A process in accordance with claim 1further including, prior to said step (d), contacting phages from thesecond group produced in step (c) with a serum sample from a thirdpatient whose serum contains antibodies to the antigen or pathogenicorganism and selecting a third group of phages that are bound byantibodies present in samples from all of said first, second and thirdpatients, wherein the phages from the second group as used in step (d)comprise phages from the third group.
 3. A process in accordance withclaim 1, wherein said phage-displayed random peptide library is oneprepared using filamentous phages selected from the group consisting ofM13, F1, Fd and derivatives thereof.
 4. A process in accordance withclaim 1, wherein said phage-displayed random peptide library is one inwhich the random sequence oligonucleotidic inserts are inserted into thegene coding for protein VIII of the phage capsid.
 5. A process inaccordance with claim 3, wherein said phage-displayed random peptidelibrary is one in which the random sequence oligonucleotidic inserts areinserted into the gene coding for protein III of the phage capsid.
 6. Aprocess in accordance with claim 1, wherein said antigen or pathogenicorganism is one selected from the group consisting of the surfaceantigen of the virus of human hepatitis B (HBsAg), the virus of humanhepatitis C, and antigens pathogenically linked to an autoimmunedisease.
 7. A process in accordance with claim 6, wherein the patient isone who has been immunized with HBsAg or one infected with the virus ofhuman hepatitis C.
 8. A process in accordance with claim 1, wherein saidphage-displayed random peptide library is one in which the randomsequence oligonucleotide inserts are inserted using the plasmid pc89 asa vector.